A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

NCT ID: NCT02264574

Last Updated: 2020-09-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 229 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-10-06
• Study Completion Date: 2019-09-03

Brief Summary

The primary objective of this study is to evaluate the efficacy of ibrutinib in combination with obinutuzumab compared to chlorambucil in combination with obinutuzumab based on the Independent Review Committee (IRC) assessment of progression free survival (PFS). Efficacy will be evaluated according to 2008 International Workshop for Chronic Lymphocytic Leukemia (IWCLL) criteria with the modification for treatment-related lymphocytosis, in subjects with treatment-naive CLL or SLL.

Conditions

Chronic Lymphocytic Leukemia; Small-Cell Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

IBR + OB

Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Ibrutinib

Intervention Type: DRUG

Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) administration.

Obinutuzumab

Intervention Type: DRUG

Obinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration

CLB + OB

Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity.

Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Obinutuzumab

Intervention Type: DRUG

Obinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration

Chlorambucil

Intervention Type: DRUG

Chlorambucil will be supplied as 2 mg film-coated tablets for oral (PO) administration

Interventions

Ibrutinib

Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) administration.

Intervention Type: DRUG

Obinutuzumab

Obinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration

Intervention Type: DRUG

Chlorambucil

Chlorambucil will be supplied as 2 mg film-coated tablets for oral (PO) administration

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Disease Related:

1. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.

2. Age 65 yrs and older OR if less than 65 years, must have at least one of the following criteria:

• Cumulative Illness Rating Score (CIRS) >6
• Creatinine clearance estimated <70 mL/min using Cockcroft-Gault equation.
• Del 17p by fluorescence in situ hybridization (FISH) or TP53 mutation by polymerase chain reaction (PCR) or Next Generation Sequencing

3. Active disease meeting at least 1 of the following IWCLL criteria for requiring treatment:

• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and thrombocytopenia
• Massive, progressive, or symptomatic splenomegaly
• Massive nodes (at least 10 cm longest diameter), or progressive or symptomatic lymphadenopathy.
• Progressive lymphocytosis with an increase of more than 50 percent over a 2-month period or a lymphocyte doubling time (LDT) of <6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of <30,000/µL, LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
• Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy.
• Autoimmune hemolytic anemia is defined by at least one marker of hemolysis (indirect bilirubin above the upper limit of normal (ULN) not due to liver disease, increased lactate dehydrogenase (above ULN) without alternative etiology, or increased absolute reticulocytosis (above ULN) or bone marrow erythropoiesis in the absence of bleeding AND at least one marker direct or indirect autoimmune mechanism (positive direct antiglobulin for immunoglobulin G [IgG] or C3d, cold agglutinins).
• Immune thrombocytopenia is defined by platelets ≤100,000/µL and increased megakaryocytes on the bone marrow exam.
• Constitutional symptoms, defined as one or more of the following disease-related symptoms or signs, documented in the patient's record prior to randomization:
• unintentional weight loss >10 percent within 6 months prior to screening.
• significant fatigue (inability to work or perform usual activities).
• fevers >100.5°F or 38.0°C for 2 or more weeks prior to screening without evidence of infection.
• night sweats for more than 1 month prior to screening without evidence of infection.

4. Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node >1.5 cm in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.

Laboratory

5. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening and randomization.

6. Adequate hepatic and renal function

7. Men and women ≥ 18 years of age.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Exclusion Criteria

1. Any prior treatment of CLL or SLL

2. Evidence of central nervous system (CNS) involvement with primary disease of CLL/SLL

3. History of other malignancies, except:

• Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.

4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura

5. Known or suspected history of Richter's transformation.

6. Concurrent administration of >20mg/day of prednisone within 7 days of randomization unless indicated for prophylaxis or management of allergic reactions (eg, contrast)

7. Known hypersensitivity to one or more study drugs

8. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

9. Any uncontrolled active systemic infection or an infection requiring systemic treatment that was completed ≤ 7 days before randomization.

10. Known bleeding disorders or hemophilia.

11. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

12. Known history of human immunodeficiency virus (HIV) or active with hepatitis B virus (HBV) or hepatitis C virus (HCV).

13. Major surgery within 4 weeks of randomization.

14. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.

15. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.

16. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

17. Concomitant use of warfarin or other vitamin K antagonists.

18. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.

19. Lactating or pregnant

20. Unwilling or unable to participate in all required study evaluations and procedures.

21. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pharmacyclics LLC.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lori Styles

Role: STUDY_DIRECTOR

Pharmacyclics LLC.

Locations

Site Reference ID/Investigator# 0241

La Jolla, California, United States

Site Reference ID/Investigator# 0844

Fort Myers, Florida, United States

Site Reference ID/Investigator# 0763

West Palm Beach, Florida, United States

Site Reference ID/Investigator# 071

Louisville, Kentucky, United States

Site Reference ID/Investigator# 0712

Las Vegas, Nevada, United States

Site Reference ID/Investigator# 0845

Cincinnati, Ohio, United States

Site Reference ID/Investigator# 0868

Chattanooga, Tennessee, United States

Site Reference ID/Investigator# 0123

Nashville, Tennessee, United States

Site Reference ID/Investigator #0503

Woolloongabba, Queensland, Australia

Site Reference ID/Investigator# 0650

Adelaide, South Australia, Australia

Site Reference ID/Investigator# 0888

Ballarat, Victoria, Australia

Site Reference ID/Investigator# 0193

Box Hill, Victoria, Australia

Site Reference ID/Investigator# 0633

Fitzroy, Victoria, Australia

Site Reference ID/Investigator# 0170

Heidelberg, Victoria, Australia

Site Reference ID/Investigator# 0352

Linz, , Austria

Site Reference ID/Investigator# 0869

Salzburg, , Austria

Site Reference ID/Investigator# 0559

Leuven, , Belgium

Site Reference ID/Investigator# 0850

Turnhout, , Belgium

Site Reference ID/Investigator# 018

Edmonton, Alberta, Canada

Site Reference ID/Investigator# 0564

Hradec Králové, , Czechia

Site Reference ID/Investigator# 0854

Prague, , Czechia

Site Reference ID/Investigator# 0769

Pessac, Gironde, France

Site Reference ID/Investigator# 0520

Nantes, Loire Atlantique, France

Site Reference ID/Investigator# 0775

Vandœuvre-lès-Nancy, Meurthe Et Moselle, France

Site Reference ID/Investigator# 0855

Bayonne, Pyrenees Atlantiques, France

Site Reference ID/Investigator# 0573

Haifa, , Israel

Site Reference ID/Investigator# 0577

Jerusalem, , Israel

Site Reference ID/Investigator# 0579

Jerusalem, , Israel

Site Reference ID/Investigator# 0575

Petah Tikva, , Israel

Site Reference ID/Investigator# 0856

Tel Aviv, , Israel

Site Reference ID/Investigator# 0875

Ẕerifin, , Israel

Site Reference ID/Investigator# 0860

Florence, , Italy

Site Reference ID/Investigator# 0523

Milan, , Italy

Site Reference ID/Investigator# 0581

Milan, , Italy

Site Reference ID/Investigator# 0584

Milan, , Italy

Site Reference ID/Investigator# 0524

Modena, , Italy

Site Reference ID/Investigator# 0582

Novara, , Italy

Site Reference ID/Investigator# 0732

Roma, , Italy

Site Reference ID/Investigator# 0859

Siena, , Italy

Site Reference ID/Investigator# 0663

Auckland, , New Zealand

Site Reference ID/Investigator# 662

Auckland, , New Zealand

Site Reference ID/Investigator# 0586

Hamilton, , New Zealand

Site Reference ID/Investigator# 0592

Brzozów, , Poland

Site Reference ID/Investigator# 0531

Lodz, , Poland

Site Reference ID/Investigator# 0708

Nizhny Novgorod, , Russia

Site Reference ID/Investigator# 0707

Ryazan, , Russia

Site Reference ID/Investigator# 0881

Saint Petersburg, , Russia

Site Reference ID/Investigator# 710

Saint Petersburg, , Russia

Site Reference ID/Investigator# 304

Yaroslavl, , Russia

Site Reference ID/Investigator# 0604

L'Hospitalet de Llobregat, Madrid, Spain

Site Reference ID/Investigator# 0536

Majadahonda, Madrid, Spain

Site Reference ID/Investigator# 0533

Barcelona, , Spain

Site Reference ID/Investigator# 0534

Barcelona, , Spain

Site Reference ID/Investigator# 0535

Barcelona, , Spain

Site Reference ID/Investigator# 0537

Madrid, , Spain

Site Reference ID/Investigator# 0864

Madrid, , Spain

Site Reference ID/Investigator# 0874

Madrid, , Spain

Site Reference ID/Investigator# 0790

Salamanca, , Spain

Site Reference ID/Investigator# 0870

Borås, , Sweden

Site Reference ID/Investigator# 0865

Luleå, , Sweden

Site Reference ID/Investigator# 0631

Lund, , Sweden

Site Reference ID/Investigator# 0632

Stockholm, , Sweden

Site Reference ID/Investigator# 0678

Istanbul, Nisantasi, Turkey (Türkiye)

Site Reference ID/Investigator# 0608

Ankara, , Turkey (Türkiye)

Site Reference ID/Investigator# 606

Ankara, , Turkey (Türkiye)

Site Reference ID/Investigator# 0889

Denizli, , Turkey (Türkiye)

Site Reference ID/Investigator# 0601

Izmir, , Turkey (Türkiye)

Site Reference ID/Investigator# 0866

Samsun, , Turkey (Türkiye)

Site Reference ID/Investigator# 0867

Harlow, Essex, United Kingdom

Site Reference ID/Investigator# 0365

London, , United Kingdom

Site Reference ID/Investigator# 0543

London, , United Kingdom

Countries

United States; Australia; Austria; Belgium; Canada; Czechia; France; Israel; Italy; New Zealand; Poland; Russia; Spain; Sweden; Turkey (Türkiye); United Kingdom

References

Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5. Epub 2018 Dec 3.

Reference Type: RESULT

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Reference Type: DERIVED

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Reference Type: DERIVED

PMID: 35014928 (View on PubMed)

Allan JN, Shanafelt T, Wiestner A, Moreno C, O'Brien SM, Li J, Krigsfeld G, Dean JP, Ahn IE. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022 Feb;196(4):947-953. doi: 10.1111/bjh.17984. Epub 2021 Dec 5.

Reference Type: DERIVED

PMID: 34865212 (View on PubMed)

Greil R, Tedeschi A, Moreno C, Anz B, Larratt L, Simkovic M, Gill D, Gribben JG, Flinn IW, Wang Z, Cheung LWK, Nguyen AN, Zhou C, Styles L, Demirkan F. Pretreatment with ibrutinib reduces cytokine secretion and limits the risk of obinutuzumab-induced infusion-related reactions in patients with CLL: analysis from the iLLUMINATE study. Ann Hematol. 2021 Jul;100(7):1733-1742. doi: 10.1007/s00277-021-04536-6. Epub 2021 May 20.

Reference Type: DERIVED

PMID: 34018029 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

PCYC-1130-CA

Identifier Type: -

Identifier Source: org_study_id